Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
Authors: Xueya Zhou, Pamela Feliciano, Chang Shu, Tianyun Wang, Irina Astrovskaya, Jacob B. Hall, Joseph U. Obiajulu, Jessica R. Wright, Shwetha C. Murali, Simon Xuming Xu, Leo Brueggeman, Taylor R. Thomas, Olena Marchenko, Christopher Fleisch, Sarah D. Barns, LeeAnne Green Snyder, Bing Han, Timothy S. Chang, Tychele N. Turner, William T. Harvey, Andrew Nishida, Brian J. O’Roak, Daniel H. Geschwind, Adrienne Adams, Alpha Amatya, Alicia Andrus, Asif Bashar, Anna Berman, Alison Brown, Alexies Camba, Amanda C. Gulsrud, Anthony D. Krentz, Amanda D. Shocklee, Amy Esler, Alex E. Lash, Anne Fanta, Ali Fatemi, Angela Fish, Alexandra Goler, Antonio Gonzalez, Anibal Gutierrez, Antonio Hardan, Amy Hess, Anna Hirshman, Alison Holbrook, Andrea J. Ace, Anthony J. Griswold, Angela J. Gruber, Andrea Jarratt, Anna Jelinek, Alissa Jorgenson, A. Pablo Juarez, Annes Kim, Alex Kitaygorodsky, Addie Luo, Angela L. Rachubinski, Allison L. Wainer, Amy M. Daniels, Anup Mankar, Andrew Mason, Alexandra Miceli, Anna Milliken, Amy Morales-Lara, Alexandra N. Stephens, Ai Nhu Nguyen, Amy Nicholson, Anna Marie Paolicelli, Alexander P. McKenzie, Abha R. Gupta, Ashley Raven, Anna Rhea, Andrea Simon, Aubrie Soucy, Amy Swanson, Anthony Sziklay, Amber Tallbull, Angela Tesng, Audrey Ward, Allyson Zick, Brittani A. Hilscher, Brandi Bell, Barbara Enright, Beverly E. Robertson, Brenda Hauf, Bill Jensen, Brandon Lobisi, Brianna M. Vernoia, Brady Schwind, Bonnie VanMetre, Craig A. Erickson, Catherine A. W. Sullivan, Charles Albright, Claudine Anglo, Cate Buescher, Catherine C. Bradley, Claudia Campo-Soria, Cheryl Cohen, Costanza Colombi, Chris Diggins, Catherine Edmonson, Catherine E. Rice, Carrie Fassler, Catherine Gray, Chris Gunter, Corrie H. Walston, Cheryl Klaiman, Caroline Leonczyk, Christa Lese Martin, Catherine Lord, Cora M. Taylor, Caitlin McCarthy, Cesar Ochoa-Lubinoff, Crissy Ortiz, Cynthia Pierre, Cordelia R. Rosenberg, Chris Rigby, Casey Roche, Clara Shrier, Chris Smith, Candace Van Wade, Casey White-Lehman, Christopher Zaro, Cindy Zha, Dawn Bentley, Dahriana Correa, Dustin E. Sarver, David Giancarla, David G. Amaral, Dain Howes, Dalia Istephanous, Daniel Lee Coury, Deana Li, Danica Limon, Desi Limpoco, Diamond Phillips, Desiree Rambeck, Daniela Rojas, Diksha Srishyla, Danielle Stamps, Dennis Vasquez Montes, Daniel Cho, Dave Cho, Emily A. Fox, Ethan Bahl, Elizabeth Berry-Kravis, Elizabeth Blank, Erin Bower, Elizabeth Brooks, Eric Courchesne, Emily Dillon, Erin Doyle, Erin Given, Ellen Grimes, Erica Jones, Eric J. Fombonne, Elizabeth Kryszak, Ericka L. Wodka, Elena Lamarche, Erica Lampert, Eric M. Butter, Eirene O’Connor, Edith Ocampo, Elizabeth Orrick, Esmeralda Perez, Elizabeth Ruzzo, Emily Singer, Emily T. Matthews, Ernest V. Pedapati, Faris Fazal, Fiona K. Miller, Gabriella Aberbach, Gabriele Baraghoshi, Gabrielle Duhon, Gregory Hooks, Gregory J. Fischer, Gabriela Marzano, Gregory Schoonover, Gabriel S. Dichter, Gabrielle Tiede, Hannah Cottrell, Hannah E. Kaplan, Haidar Ghina, Hanna Hutter, Hope Koene, Hoa Lam Schneider, Holly Lechniak, Hai Li, Hadley Morotti, Hongjian Qi, Harper Richardson, Hana Zaydens, Haicang Zhang, Haoquan Zhao, Ivette Arriaga, Ivy F. Tso, John Acampado, Jennifer A. Gerdts, Josh Beeson, Jennylyn Brown, Joaquin Comitre, Jeanette Cordova, Jennifer Delaporte, Joseph F. Cubells, Jill F. Harris, Jared Gong, Jaclyn Gunderson, Jessica Hernandez, Jessyca Judge, Jane Jurayj, J. Kiely Law, Julie Manoharan, Jessie Montezuma, Jason Neely, Jessica Orobio, Juhi Pandey, Joseph Piven, Jose Polanco, Jibrielle Polite, Jacob Rosewater, Jessica Scherr, James S. Sutcliffe, James T. McCracken, Jennifer Tjernagel, Jaimie Toroney, Jeremy Veenstra-Vanderweele, Jiayao Wang, Katie Ahlers, Kathryn A. Schweers, Kelli Baalman, Katie Beard, Kristen Callahan, Kendra Coleman, Kate D. Fitzgerald, Kate Dent, Katharine Diehl, Kelsey Gonring, Katherine G. Pawlowski, Kathy Hirst, Karen L. Pierce, Karla Murillo, Kailey Murray, Kerri Nowell, Kaela O’Brien, Katrina Pama, Kelli Real, Kaitlyn Singer, Kaitlin Smith, Kevin Stephenson, Katherine Tsai, Leonard Abbeduto, Lindsey A. Cartner, Landon Beeson, Laura Carpenter, Lucas Casten, Leigh Coppola, Lisa Cordiero, Lindsey DeMarco, Lillian D. Pacheco, Lorena Ferreira Corzo, Lisa H. Shulman, Lauren Kasperson Walsh, Laurie Lesher, Lynette M. Herbert, Lisa M. Prock, Lacy Malloch, Lori Mann, Luke P. Grosvenor, Laura Simon, Latha V. Soorya, Lucy Wasserburg, Lisa Yeh, Lark Y. Huang-Storms, Michael Alessandri, Marc A. Popp, Melissa Baer, Malia Beckwith, Myriam Casseus, Michelle Coughlin, Mary Currin, Michele Cutri, Malcolm D. Mallardi, Megan DuBois, Megan Dunlevy, Martin E. Butler, Margot Frayne, McLeod F. Gwynette, Mohammad Ghaziuddin, Monica Haley, Michelle Heyman, Margaret Hojlo, Michelle Jordy, Michael J. Morrier, Misia Kowanda, Melinda Koza, Marilyn Lopez, Megan McTaggart, Megan Norris, Melissa N. Hale, Molly O’Neil, Madison Printen, Madelyn Rayos, Mahfuza Sabiha, Mustafa Sahin, Marina Sarris, Mojeeb Shir, Matthew Siegel, Morgan Steele, Megan Sweeney, Maira Tafolla, Maria Valicenti-McDermott, Mary Verdi, Megan Y. Dennis, Nicolas Alvarez, Nicole Bardett, Natalie Berger, Norma Calderon, Nickelle Decius, Natalia Gonzalez, Nina Harris, Noah Lawson, Natasha Lillie, Nathan Lo, Nancy Long, Nicole M. Russo-Ponsaran, Natalie Madi, Nicole Mccoy, Natalie Nagpal, Nicki Rodriguez, Nicholas Russell, Neelay Shah, Nicole Takahashi, Nicole Targalia, Olivia Newman, Opal Y. Ousley, Peter Heydemann, Patricia Manning, Paul S. Carbone, Raphael A. Bernier, Rachel A. Gordon, Rebecca C. Shaffer, Robert D. Annett, Renee D. Clark, Roger Jou, Rebecca J. Landa, Rachel K. Earl, Robin Libove, Richard Marini, Ryan N. Doan, Robin P. Goin-Kochel, Rishiraj Rana, Richard Remington, Roman Shikov, Robert T. Schultz, Shelley Aberle, Shelby Birdwell, Sarah Boland, Stephanie Booker, S. Carpenter, Sharmista Chintalapalli, Sarah Conyers, Sophia D’Ambrosi, Sara Eldred, Sunday Francis, Swami Ganesan, Susan Hepburn, Susannah Horner, Samantha Hunter, Stephanie J. Brewster, Soo J. Lee, Suma Jacob, Stanley Jean, So Hyun, Sydney Kramer, Sandra L. Friedman, Sarely Licona, Sandy Littlefield, Stephen M. Kanne, Sarah Mastel, Sheena Mathai, Sophia Melnyk, Sarah Michaels, Sarah Mohiuddin, Samiza Palmer, Samantha Plate, Shanping Qiu, Shelley Randall, Sophia Sandhu, Susan Santangelo, Swapnil Shah, Steve Skinner, Samantha Thompson, Sabrina White, Stormi White, Sabrina Xiao, Sidi Xu, Simon Xu, Tia Chen, Tunisia Greene, Theodore Ho, Teresa Ibanez, Tanner Koomar, Tiziano Pramparo, Tara Rutter, Tamim Shaikh, Thao Tran, Timothy W. Yu, Virginia Galbraith, Vahid Gazestani, Vincent J. Myers, Vaikunt Ranganathan, Vini Singh, William Curtis Weaver, Wenteng CaI, Wubin Chin, Wha S. Yang, Y. B. Choi, Zachary E. Warren, Jacob J. Michaelson, Natalia Volfovsky, Evan E. Eichler, Yufeng Shen, Wendy K. Chung
Journal: Nature Genetics (2022)

Abstract To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance ( P &lt; 2.5 × 10 −6 ), including five new risk genes ( NAV3 , ITSN1 , MARK2 , SCAF1 and HNRNPUL2 ). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes ( NAV3 , ITSN1 , SCAF1 and HNRNPUL2 ; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes ( CHD8, SCN2A, ADNP, FOXP1 and SHANK3 ) (59% vs 88%, P = 1.9 × 10 −6 ). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.